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β -lactamase inhibitors

β -lactamase inhibitors. Almost all have weak antibacterial activity. Important in combination with penicillins sensitive to β -lactamase degradation. Clavulanic acid is the first one of this class. Natural product from streptomyces.

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β -lactamase inhibitors

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  1. β-lactamase inhibitors • Almost all have weak antibacterial activity. • Important in combination with penicillins sensitive to β-lactamase degradation. • Clavulanic acid is the first one of this class. • Natural product from streptomyces. • Has a powerful and irreversible inhibition of β-lactamase enzymes because it will covalently bind to two positions in the active site. • Normally used in combination with amoxicillin and other β-lactamase sensitive penicillins

  2. SAR for β-lactamase inhibitors • β-lactam ring is essential. • The enol ether have a rule in binding. • The elkene moiety should have Z configuration which is much more active than the E isomer. • No substitution at C6. • R stereochemistry at C3. • Carboxylic acid at C3 is essential.

  3. Cephalosporins. • The first agent discovered was cephalosporin C, obtained from the fungus cephalosporiumacremonium. • 1/1000 the antibacterial activity of penicillin G. • Has the same mechanism of action as penicillins (inhibits cell wall cross linking). • Has greater stability toward acid and β-lactamase.

  4. SAR of cephalosporins • The bicyclic system is essential. • The carboxylic acid at C4 is essential. • Acylamino group at C7 is essential. • Acetyloxy group at C3 is important and act as a leaving group when the molecule binds to transpeptidase.

  5. Synthesis of Cephalosporins • Unlike 6-APA, 7ACA was difficult to isolate and purify. • Instead, 7ACA was synthesized from cephalosporin C as follows

  6. 1st Generation Cephalosporins • Have lower activity than penicillin but they have broader spectrum action. • Still susceptible to β-lactamase degradation. • Steric shield helped to improve stability toward β-lactamase degradation but proved to reduce antibacterial activity.

  7. 1st Generation Cephalosporins • Have the good leaving group, pyridinium ion.. This improved activity. • This group is not hydrolysable compared to the acetyloxy group found in cephalothin. • Poorly absorbed from the gut because it will be ionized all the time. • Only given parenterally.

  8. 2nd Generation Cephalosporins • They have methoxy group at C7 which make them active against the resistant strains. • They have a carbamate group at C3 that increase stability toward hydrolysis compared to the acetyloxy group found in 1st generation derivatives.

  9. 2nd Generation Cephalosporins • Other agents are the oximinocephalosporins: • Have the iminomethoxy group at the α-carbon in the acyl side chain, this increased stability toward β-lactamase.

  10. 3rd Generation Cephalosporins • Here the aminothiazole ring has replaced the furan ring of cefuroxime: • This enhanced the penetration through the outer membrane of gram –ve bacteria, • Increase the affinity for transpeptidase. • Not recommended as first line therapy to prevent the rapid development of resistance.

  11. 3rd Generation Cephalosporins • Cefdinir (Omnicef®): • It has a broad spectrum activity. • More active on gram –ve bacterial infections such as respiratory, skin and soft tissues infections. • Estimated oral bioavailability is 20-25% (WHY?). • LogP = 0.02 • pKa = 3.27

  12. 4th Generation Cephalosporins • They have a positively charged group at C3 which become a good leaving group during the binding with transpeptidase. • They are more polar than the old generation, better penetration for the outer membrane of gram –ve bacteria. • More stable toward β-lactamase.

  13. New generation Cephalosporins Cephtobiprole • 5th generation cephalosporin (2008). • Only given IV (Why?). • Resistant to staphylococcal β-lactamase (Why?). • activity against methicillin-resistant S. aureus, penicillin-resistant S. pneumoniae, P. aeruginosa, and Enterococci.

  14. New generation Cephalosporins Cefsulodin • 3rd generation cephalosporin. • has very specific activity against P. aeruginosa. • limited activity against Gram-positive bacteria and anaerobic bacteria. • Is not clinically used nowadays (difficult to purify during synthesis).

  15. New generation Cephalosporins Ceftaroline • 5th generation cephalosporins. • It retains the activity of later generation cephalosporins having broad spectrum activity against Gram -ve and gram +ve bacteria especially on resistant strains. • Approved for clinical use in USA in 2010. • Still in clinical trials (phase III).

  16. New generation Cephalosporins Cefmenoxime • 3rd generation cephalosporins. • It is mainly active on gram –ve bacteria. • Only available as intramuscular injections. • LogP = - 0.87

  17. New generation Cephalosporins Predict its pharmacokinetic and activity profile?

  18. Carbapenems • No thiazolidine or dihydrothiazine ring. • They have two strained rings which decrease the chemical stability as well as acid stability. • The inverse stereochemistry at C6 and the presence of hydroxyl group increase stability toward β-lactamase enzymes. • They have broad spectrum activity.

  19. Monobactams • It has a limited activity against gram +ve bacteria. • Because it does not have the fused ring system, Aztreonam is believed to have different mechanism of action.. • highly polar structure which reduce the oral bioavailability… it is recommended to be given parenterally

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